Nivolumab Shows Durable Activity in Subgroups of Patients with Metastatic CRC

Almost 66% of patients who had previously received treatment for metastatic co­lorectal cancer (mCRC) and DNA mismatch repair deficiency (dMMR) derived clinical benefit from monotherapy with nivolumab (Opdivo), long-term follow-up from a prospective clinical trial showed. After a median follow-up of almost 2 years, 34% of 74 evaluable patients had objective responses, including 7 complete responses.

An additional 31% of patients had stable disease. The duration of response was as high as 31.6 months, and 66% of responses lasted ≥12 months. Furthermore, most patients (70%-80%) were alive at 18 months, as reported at the 2018 Gastrointestinal Cancers Symposium.

“Nivolumab continued to provide durable clinical benefit with long-term follow-up in previously treated patients with DNA mismatch repair deficiency and microsatellite instability-high [MSI-H] metastatic co­lorectal cancer,” said Michael J. Overman, MD, Committee Chair, Department of Gastrointestinal Medical Oncology, Pharmacy & Therapeutics Committee, M.D. Anderson Cancer Center, Houston, who presented the results.

“We observed durable clinical benefit with deepening of responses, regardless of prior chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan.”


The CheckMate-142 clinical trial focused on a subgroup of patients with mCRC associated with dMMR and MSI-H tumors, which account for about 4% of all mCRC. The trial’s design followed preliminary evidence of meaningful clinical benefit in that subgroup. A preliminary analysis of data from the study after 13 months of follow-up showed an objective response rate (ORR) of 32%, and 75% of the patients were alive at 1 year (Overman MJ, et al. Lancet Oncol. 2017;18:1182-1191).

The FDA granted accelerated approval to nivolumab based on a notable clinical benefit in a subset of patients who progressed after receiving the standard first-line chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan. Dr Overman presented an updated analysis of the CheckMate-142 study.

All patients had received ≥1 lines of systemic therapy. The 74 patients consisted of 53 whose treatment history included exposure to the chemotherapy regimen, and 21 who did not receive all 3 drugs.

Of these patients (median age, 52.5 years), 45% had stage IV mCRC, a majority had BRAF or KRAS mutations, and 38% had a history of Lynch syndrome.

After a median follow-up of 21 months, the ORR had increased slightly from 32% at 13 months to 34%. The clinical benefit rate was 64%, consisting of 7 complete responses (9%), 18 partial responses (24%), and stable disease in 23 patients (31%). An increase in complete responses (2 at 13 months vs 7 at 21 months) and a decrease in partial responses (22 at 13 months vs 18 at 21 months) indicated a deepening of response over time.

The median duration of response had yet to be reached, and the median duration of stable disease was 8.3 months.

“The median time to response was approximately 2.8 months across all subgroups, and clinical benefit was observed across all subgroups,” Dr Overman said. “Overall, 60% of patients had some reduction in tumor burden from baseline with nivolu­mab monotherapy.”

The study population had a median progression-free survival (PFS) of 6.6 months and did not differ between the 2 subgroups specified for the analysis. The PFS at 12 and 18 months was 44%, which was slightly higher in patients without exposure to all 3 chemotherapies (52%) compared with patients with a history of the chemotherapy regimen (41%).

Overall survival (OS) was 60% at 12 months and 54.9% at 18 months. The subgroup analysis showed a median OS of 68% at 12 months and 66% at 18 months for patients with exposure to all 3 chemotherapies. Corresponding rates for patients without exposure to all 3 drugs were 81% at 12 months and 70% at 18 months. No patient who responded to treatment had died as of the data cutoff.

Overall, 75% of patients had treatment-related adverse events, reaching grade 3 or 4 severity in 20% of patients, and 8% of patients discontinued treatment because of adverse events. The most common adverse events (all grades) were fatigue (23%), diarrhea (22%), pruritus (16%), lipase increase (12%, including 8% grade 3 or 4), and rash (11%).

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